The present invention relates to a method of selectively producing 3-alkoxy-1,3,5(10)-triene-6-one-steroid derivatives, which are useful for drugs and diagnostic agents.
Conventionally, there has been disclosed, in Steroids, 59, 621 (1994), a method for producing 3-alkoxy-1,3,5(10)-triene-6-one-steroid derivatives (hereinafter referred to as 3-alkoxytriene steroids) having, in the steroid skeleton thereof, a partial structure of A- and B-rings represented by formula (2): 
(wherein R represents an alkyl group, a cycloalkyl group, an alkenyl group, or an aralkyl group) from 19-norsteroid derivatives (hereinafter referred to as 19-norsteroids) having, in the steroid skeleton thereof, a partial structure of A- and B-rings represented by formula (1): 
by the reaction, in methanol, of 19-nor-4-androstene-3,17-dione with iodine in the presence of ceric ammonium nitrate as a rare earth compound catalyst, to thereby yield estrone-methyl ether (predominant product) and oxoestrone-methyl ether (by-product) in the form of a mixture. However, this method is not industrially efficient, since it involves a reaction employing a rare earth metal compound catalyst which requires burdensome waste treatment; the yield of 6-one species is as low as 23-27%; and high-cost silica gel column chromatography must be carried out so as to separate from by-product and purify the target compound.
As stated above, the conventional technique is not preferred as a method for industrially producing 3-alkoxytriene-6-one steroids from 19-norsteroids.
Accordingly, an object of the present invention is to provide a method for industrially producing 3-alkoxytriene-6-one steroids from 19-norsteroids in a simple manner, with high efficiency and high safety, at low costs, and employing neither a special apparatus nor a reagent raises problems in terms of waste treatment.
The present inventors have carried out extensive studies, and quite unexpectedly, have found that when 19-norsteroid is reacted with alcohol and iodine in the absence of a rare earth compound, which may serve as an oxidizing agent, a 6-oxo species can be obtained selectively, as contrasted to the case of the presence of a rare earth compound catalyst, whereby the aforementioned 6-desoxo species is predominantly produced. The present invention has been accomplished on the basis of this finding.
Accordingly, the present invention provides a method of producing 3-alkoxy-1,3,5(10)-triene-6-one-steroid derivatives having, in the steroid skeleton thereof, a partial structure of A- and B-rings represented by formula (2): 
(wherein R represents an alkyl group, a cycloalkyl group, an alkenyl group, or an aralkyl group), comprising reacting a 19-norsteroid derivative having, in the steroid skeleton thereof, a partial structure of A- and B-rings represented by formula (1): 
with an alcohol represented by ROH (wherein R has the same meaning as defined above) and iodine in the absence of a rare earth compound catalyst.
The production method of the present invention is represented by the following reaction scheme: 
(wherein R has the same meaning as defined above).
In the present invention, any 3-oxo-4-ene-19-norsteroids having, in the steroid skeleton thereof, a partial structure of A- and B-rings represented by the above formula (1) may be employed as a starting material. They may be of natural origin, semi-synthesized, or synthesized. These 19-norsteroids may have any number of substituent at any position of the rings constituting the steroid skeleton (represented by the below-described structure of formula (3)), so long as the substituent or the position of substitution does not affect the reaction according to the present invention. Examples of the position of substitution which does not affect the reaction according to the present invention include 11-, 12-, 15-, 16-, and 17-positions. 
Examples of the substituent which does not affect the reaction according to the present invention include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), a hydroxyl group, acyloxy groups having a total carbon number of 2 to 7, optionally substituted alkyl groups having a total carbon number of 1 to 10, optionally substituted acyl groups having have a total carbon number of 1 to 7, optionally substituted aralkyl groups having a carbon number of 7 to 11, alkenyl groups having a carbon number of 2 to 4, alkynyl groups having a carbon number of 2 to 4, and optionally substituted alkylidene groups having a carbon number of 1 to 4.
Examples of the acyloxy groups having a carbon number of 2 to 7 include an acetyloxy group, a propionyloxy group, a butylyloxy group, an isobutylyloxy group, an isovaleryloxy group, a pivaloyloxy group, and a heptanoyloxy group.
Examples of the alkyl groups having a carbon number of 1 to 10 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, a 4-isopropylpentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group. These alkyl groups may have a substituent. Examples of the substituent include halogen atoms, a hydroxyl group, a hydroxycarbonyl group, alkoxy groups having a carbon number of 1 to 4 (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy), acyl groups having a total carbon number of 1 to 5 (e.g., formyl, acetyl, propionyl, butylyl, isobutylyl, isovaleryl, pivaloyl), aryloxy groups having a carbon number of 6 to 10 (e.g., phenoxy, naphthyloxy) which may have 1-3 substituents. Examples of the substituents of the aryloxy groups having a carbon number of 6 to 10 and optionally having 1-3 substituents include halogen atoms, a hydroxyl group, alkyl groups having a carbon number of 1 to 4 (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl), alkoxy groups having a carbon number of 1 to 4 (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy), dialkylamino groups having a total carbon number of 2 to 6 (e.g., dimethylamino, diethylamino, dipropylamino, diisopropylamino), acyl groups having a total carbon number of 1 to 4 (e.g., formyl, acetyl, propionyl, butylyl), alkoxyalkyl groups having a total carbon number of 2 to 6 (e.g., methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, isopropoxyethyl, ethoxybutyl), dialkylaminocarbonyl groups having a total carbon number of 3 to 9 (e.g., dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, dibutylaminocarbonyl), and dialkylaminoalkyl groups having a total carbon number of 3 to 9 (e.g., dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, diisopropylaminomethyl, dibutylaminomethyl).
Examples of the acyl groups having a total carbon number of 1 to 7 include a formyl group, an acetyl group, a propionyl group, a butylyl group, an isobutylyl group, an isovaleryl group, a pivaloyl group, and a heptanoyl group. The substituents which may be incorporated into these acyl groups include the aforementioned examples of the substituents of the optionally substituted alkyl groups.
Examples of the aralkyl groups having a carbon number of 7 to 11 include a benzyl group, a phenetyl group, a phenylpropyl group, and a naphthylmethyl group. The substituents which may be incorporated into these aralkyl groups include the aforementioned examples of the substituents of the optionally substituted alkyl groups.
Examples of the alkenyl groups having a carbon number of 2 to 4 include a vinyl group, an allyl group, an isopropenyl group, and a 2-butenyl group. Examples of the alkynyl groups having a carbon number of 2 to 4 include an ethynyl group, a 2-propynyl group, and 2-butynyl group.
Examples of the alkylidene groups having a carbon number of 1 to 4 include a methylidene group, an ethylidene group, and a propylidene group. The substituents which may be incorporated into these alkylidene groups include the aforementioned examples of the substituents of the optionally substituted alkyl groups as well as alkoxycarbonyl groups having a total carbon number of 2 to 7 (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl).
Examples of alcohols represented by ROH include linear or branched lower alcohols having a carbon number of 1 to 6, cycloalkanol having a carbon number of 3 to 6, allyl alcohol, and benzyl alcohol. Examples of the linear or branched lower alcohols having a carbon number of 1 to 6 include methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, t-butanol, pentanol, and hexanol. Examples of the cycloalkanol having a carbon number of 3 to 6 include cyclopropanol, cyclobutanol, cyclopentanol, and cyclohexanol. Of these, methanol, ethanol, n-propanol, isopropanol, allyl alcohol, and benzyl alcohol are preferably employed for the reaction of the present invention, with methanol, ethanol, propanol and isopropanol being more preferred.
In the method of the present invention, 19-norsteroid (1) is caused to react with iodine and alcohol (ROH) in an appropriate solvent and in the absence of a rare earth compound catalyst.
No particular limitation is imposed on the appropriate solvent, and any solvent can be used so long as it does not affect the reaction. Examples of the solvent include hydrocarbons such as benzene, toluene, and xylene; aprotic polar solvents such as acetonitrile and N,N-dimethylformamide; and ethers such as dimethoxyethane, tetrahydrofuran, and dioxane, with acetonitrile being preferred. Alcohols represented by ROH may also be used in the reaction of the present invention.
The reaction according to the present invention proceeds in the presence of oxygen, and the oxygen dissolved in the reaction mixture may suffice for this purpose. However, in order to promote the reaction on an industrial scale and enhance yield and selectivity of the target compound, additional oxygen may be supplied to the reaction mixture. Specifically, oxygen-containing gas such as air or oxygen gas is introduced into the reaction mixture. The air which is to be introduced is preferably dried by being passed through a desiccant such as calcium chloride, potassium hydroxide, sodium hydroxide, or concentrated sulfuric acid. Although the rate and time of feeding oxygen gas or air vary in accordance with conditions such as the amount of fed 19-norsteroid (1), the type and amount of solvent, and reaction temperature, the rate of feeding is preferably 1-10,000 mL/min/L, more preferably 10-8,000 mL/min/L, further more preferably 10-5,000 mL/min/L, particularly preferably 10-3,000 mL/min/L, and the time of feeding, which may vary in accordance with the rate of feeding, is preferably 0.1-8 hours, more preferably 0.5-4 hours, further more preferably 0.5-2 hours.
Iodine is preferably used in an amount of 1-8 equivalents by mol based on 19-norsteroid (1), more preferably 1-6 equivalents by mol, further more preferably 2-5 equivalents by mol. The alcohol represented by ROH is preferably used in an amount of 5-10,000 equivalents by mol based on 19-norsteroid (1), more preferably 50-1,000 equivalents by mol. The reaction temperature is preferably xe2x88x9230xc2x0 C. to 150xc2x0 C., more preferably xe2x88x9230xc2x0 C. to 120xc2x0 C., further more preferably xe2x88x9220xc2x0 C. to a temperature at which the solvent is refluxed. The reaction time for advantageously proceeding the reaction is preferably 0.1-24 hours, more preferably 0.5-12 hours, further more preferably 1-6 hours. In a particularly preferred mode, the reaction is carried out at xe2x88x9220xc2x0 C. to 30xc2x0 C. concomitant with passage of oxygen or air in an initial stage and, subsequently at 50-90xc2x0 C., although the conditions may vary in accordance with the type of alcohol (ROH) employed.
The 3-alkoxytriene steroid (2) obtained through the method of the present invention may be isolated and purified through any of generally known isolation-purification methods such as recrystallization and silica gel chromatography.